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Journal of Nucleic Acids
Volume 2010, Article ID 597098, 10 pages
http://dx.doi.org/10.4061/2010/597098
Research Article

Modulation of the Ribonucleotide Reductase-Antimetabolite Drug Interaction in Cancer Cell Lines

1Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
2Department of Oncology, Karmanos Cancer Institute, Detroit, MI 48201, USA

Received 29 March 2010; Revised 14 July 2010; Accepted 1 September 2010

Academic Editor: Caroline Kisker

Copyright © 2010 Jun Zhou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

RRM1 is a determinant of gemcitabine efficacy in cancer patients. However, the precision of predicting tumor response based on RRM1 levels is not optimal. We used gene-specific overexpression and RNA interference to assess RRM1's impact on different classes of cytotoxic agents, on drug-drug interactions, and the modulating impact of other molecular and cellular parameters. RRM1 was the dominant determinant of gemcitabine efficacy in various cancer cell lines. RRM1 also impacted the efficacy of other antimetabolite agents. It did not disrupt the interaction of two cytotoxic agents when combined. Cell lines with truncation, deletion, and null status of p53 were resistant to gemcitabine without apparent relationship to RRM1 levels. Pemetrexed and carboplatin sensitivity did not appear to be related to p53 mutation status. The impact of p53 mutations in patients treated with gemcitabine should be studied in prospective clinical trials to develop a model with improved precision of predicting drug efficacy.